Capsule-based automated synthesis for the efficient assembly of PROTAC like molecules

Abstract

In recent years, the therapeutically beneficial degradation of proteins using PROteolysis Targeting Chimeras (PROTACs) has become an increasingly popular approach in drug discovery. However, the preparation of these larger than average, heavily functionalised molecules can be synthetically challenging and time-consuming, and experience in making and handling the final PROTACs and their precursors is not yet widespread. To overcome these challenges, an existing capsule-based automated synthesis console has been adapted and employed for the automated synthesis of PROTAC-like molecules. Reagent capsules containing a partial PROTAC reagent plus the reagents required for conjugation of the partial PROTAC to the target protein binder, as well as the materials for product isolation, were prepared in order to accelerate the process and simplify PROTAC synthesis. The use of these capsules, in combination with the automated synthesis console, has enabled the safe, automated preparation of a range of different PROTAC-like molecules bearing different linker and E3 ligase functionalities.